1. Field of the Invention
This invention relates to the synthesis of 5-deazariboflavine having the formula: ##STR1## by condensing N-D-ribityl-3,4-xylidine with a novel chemical intermediate, 6-chloro-5-formyluracil.
2. Description of the Prior Art
Previously known processes for synthesizing 5-deazariboflavine include the following:
(1) A process of condensing 4,5-dimethyl-N-D-ribityl-anthranilaldehyde and barbituric acid. [Chem. Ind. (London), 204, 4-5 (1967), J. Heterocycl. Chem., 7(1), 99-105 (1970)]; ##STR2##
(2) A process of condensing 6-chlorouracil and N-D-ribityl-3,4-xylidine to obtain 6-(N-D-ribityl-3,4-xylidino)-uracil, which is acetylated with acetic anhydride in the presence of pyridine to obtain 6-[N-(tetra-O-acetyl-D-ribityl)-3,4-xylidino]-uracil, cyclizing by POCl.sub.3 in dimethylformamide under heating, and deacetylating the thus obtained tetra-O-acetyl-5-deazariboflavine by methanolic ammonia, [Angew. Chem., 88(14), 475-476 (1976), Methods in Enzymology, Vol. 66, p. 267-276 (1980)]; ##STR3##
(3) A process of condensing 2,4,6-trichloro-5-formyl-pyridine and N-D-ribityl-3,4-xylidine in dimethylformamide at room temperature, [J. Chem. Soc., Perkin I, 16, 1805-1808 (1976), Methods in Enzymology, Vol. 66, p. 267-276 (1980)]; ##STR4##
(4) A process of cyclizing 6-(N-D-ribityl-3,4-xylidino)-uracil [J. Am. Chem. Soc., 98(3), 830-835 (1976)] in dimethylformamide in the presence of triethyl orthoformate under heating [J. Chem. Soc., Perkin I, 16, 1805-1080 (1976), Methods in Enzymology, Vol. 66, p. 267-276 (1980)]; ##STR5##
(5) A process of condensing 6-chlorouracil and N-D-ribityl-3,4-xylidine in water under heating to obtain 6-(N-D-ribityl-3,4-xylidino)-uracil, then cyclizing in the presence of trimethyl orthoformate and p-toluenesulfonic acid to obtain 2',3'4'5'-bis-O-methoxymethylene-5-deazariboflavine, and heating the thus obtained product with hydrochloric acid [J. Heterocycl. Chem., 15(3), 489-491 (1978), U.S. Pat. No. 4,277,603 (July 7, 1981)]. ##STR6##
These preceding processes have a number of disadvantages.
Process (1) has many process steps and complex operations with low yield, and hence it is not an economical process.
Process (2) has many process steps, and a long synthesis, with a poor yield.
Although process (3) is a simple operable synthesis, the yield is quite low (37%) and therefore it is not industrially economical.
Process (4) is a two step synthesis, however its yield is quite low (44%) and therefore it also is not industrially economical.
Process (5) has a slightly shorter reaction process, however, its yield is low (25%) and therefore it also is not industrially economical.
5-deazariboflavine has been disclosed as a useful remedy for coccidiosis in Japanese published patent application No. 53-56698.
In the extensive discussion of Riboflavine in "The Merck Index", ninth edition, published by Merck & Co., Inc., Rahway, N.J., U.S.A. (1976) under monograph number 7993, it is stated that: "Riboflavin for therapeutic use is produced by synthesis, the most common starting materials being O-xylene, D-ribose, and alloxan". Various U.S. patents and published monographs are disclosed in monograph 7993, all of which are incorporated herein by reference. Of course riboflavine differs from the 5-deazariboflavine of this invention in that riboflavine has a nitrogen at the 5 position whereas the compound of this invention has a hydrogen (see above formula I).